Dolinska Monika, Piccini Alexandre, Wong Wan Man, Gelali Eleni, Johansson Anne-Sofie, Klang Johannis, Xiao Pingnan, Yektaei-Karin Elham, Strömberg Ulla Olsson, Mustjoki Satu, Stenke Leif, Ekblom Marja, Qian Hong
Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden.
Department of Laboratory Medicine, Lund University, Sweden.
Biochem Biophys Res Commun. 2017 Aug 19;490(2):378-384. doi: 10.1016/j.bbrc.2017.06.051. Epub 2017 Jun 13.
Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein in chronic myeloid leukemia (CML) are remarkably effective inducing deep molecular remission in most patients. However, they are less effective to eradicate the leukemic stem cells (LSC), resulting in disease persistence. Therefore, there is great need to develop novel therapeutic strategies to specifically target the LSC. In an experimental mouse CML model system, the leukotriene pathway, and specifically, the expression ALOX5, encoding 5-lipoxygenase (5-LO), has been reported as a critical regulator of the LSC. Based on these results, the 5-LO inhibitor zileuton has been introduced in clinical trials as a therapeutic option to target the LSC although its effect on primary human CML LSC has not been studied. We have here by using multiplex single cell PCR analyzed the expression of the mediators of the leukotriene pathway in bone marrow (BM) BCR-ABLCD34CD38 cells at diagnosis, and found low or undetectable expression of ALOX5. In line with this, zileuton did not exert significant overall growth inhibition in the long-term culture-initiating cell (LTC-IC) and colony (CFU-C) assays of BM CD34CD38 cells from 7 CML patients. The majority of the single leukemic BCR-ABLCD34CD38 cells expressed cysteinyl leukotriene receptors CYSLT1 and CYSLT2. However, montelukast, an inhibitor of CYSLT1, also failed to significantly suppress CFU-C and LTC-IC growth. These findings indicate that targeting ALOX5 or CYSLT1 signaling with leukotriene antagonists, introduced into the clinical practice primarily as prophylaxis and treatment for asthma, may not be a promising pharmacological strategy to eradicate persisting LSC in CML patients.
靶向慢性髓性白血病（CML）中BCR-ABL癌蛋白的酪氨酸激酶抑制剂在大多数患者中诱导深度分子缓解方面非常有效。然而，它们在根除白血病干细胞（LSC）方面效果较差，导致疾病持续存在。因此，迫切需要开发专门针对LSC的新型治疗策略。在一个实验性小鼠CML模型系统中，白三烯途径，特别是编码5-脂氧合酶（5-LO）的ALOX5的表达，已被报道为LSC的关键调节因子。基于这些结果，5-LO抑制剂齐留通已被引入临床试验，作为靶向LSC的治疗选择，尽管其对原发性人类CML LSC的作用尚未研究。我们在此通过多重单细胞PCR分析了诊断时骨髓（BM）BCR-ABL⁺CD34⁺CD38⁻细胞中白三烯途径介质的表达，发现ALOX5表达低或无法检测到。与此一致的是，齐留通在来自7例CML患者的BM CD34⁺CD38⁻细胞的长期培养起始细胞（LTC-IC）和集落（CFU-C）试验中未产生显著的总体生长抑制作用。大多数单个白血病BCR-ABL⁺CD34⁺CD38⁻细胞表达半胱氨酰白三烯受体CYSLT1和CYSLT2。然而，CYSLT1抑制剂孟鲁司特也未能显著抑制CFU-C和LTC-IC的生长。这些发现表明，主要作为哮喘预防和治疗引入临床实践的白三烯拮抗剂靶向ALOX5或CYSLT1信号传导，可能不是根除CML患者中持续存在的LSC的有前景的药理学策略。
